Coronary heart disease is the single leading cause of death in the United States. Reperfusion of the ischemic heart remains the best approach to limit necrosis and salvage the ischemic organ. It is now recognized, however, that the act of flow restoration causes additional organ damage, known as "Reperfusion Injury". It appears that the reintroduction of blood to the ischemic heart promotes the generation and release of toxins, such as oxygen radicals, which exacerbate the ischemic damage. The heart muscle and coronary circulation are particularly vulnerable to reperfusion injury, yet little is known about the role of the coronary microcirculation in this process. to effectively combat Reperfusion Injury, we must know how, when and where it happens. In this project we will investigate the pathobiology of myocardial ischemia-reperfusion (I/R) injury with particular regard to blood-coronary microvascular interactions. We will focus on the first moments of reperfusion and the participation of blood leukocytes in microvascular dysfunction. We will observe directly where and when leukocytes accumulate in the coronary microcirculation and determine the hemodynamic consequences of white cell trapping. We will investigate the properties of leukocytes that promote retention and the role of other blood components, such as platelets and complement in modulating leukostasis. We will determine if limiting leukostasis using specific pharmacologic blockers improves microvascular function. the findings from the microcirculation studies will be applied to ventricular function efficacy studies aimed to limit Reperfusion Injury. In the cardioplegia studies, we will determine if, during elective ischemia, crystalloid cardioplegia damages the coronary endothelium and enhances leukostasis during warm reperfusion. We will test the hypothesis that cardioplegia solutions, designed to preserve microvascular integrity and limit leukostasis will improve the recovery of cardiac pump function following elective ischemia. The results from the cardioplegia microcirculation experiments will be applied to efficacy studies aimed to protect the heart and improve recovery from elective ischemia. The lessons learned from these heart studies can be applied to any organ subjected to a severe reduction in blood flow.